Exosomal hnRNPA2B1 suppresses irinotecan-induced ferroptosis in pancreatic cancer.

BACKGROUND

Irinotecan is a commonly used chemotherapeutic drug for pancreatic cancer (PC), but its specific mechanism of inducing cell death is yet to be elucidated. Exosomes are key mediators of intercellular communication and are involved in tumorigenesis. This study aimed to investigate whether irinotecan-induced ferroptosis can inhibit PC progression, and to explore the mechanism of exosomes derived from PC cells reverse irinotecan-induced ferroptosis.

METHODS

Exosomes were isolated from cells via polymer precipitation method. CCK8 assay and colony formation assay were used to test the proliferation of PC cells. Wound-healing assay and Transwell migration assay were used to test the migration of PC cells. Ferroptosis in cells was detected by analysis of malondialdehyde, glutathione, Fe2+ and reactive oxygen species concentrations. Transmission electron microscopy was used to observe the morphology of intracellular mitochondria. Related proteins were detected by Western blot.

RESULTS

Irinotecan could inhibit the proliferation of PC cells, decrease the expression of the ferroptosis-negative regulators glutathione peroxidase 4 and cystine transporter solute carrier family 7 member 11, and increase the intracellular concentrations of Fe2+ and ferroptosis metabolites. However, exosomes derived from PC cells inhibit irinotecan-induced ferroptosis and diminish the anti-tumor effect, whereas this effect was significantly reduced following the knockdown of hnRNPA2B1.

CONCLUSIONS

These findings indicated that exosomal hnRNPA2B1 could inhibit irinotecan-induced ferroptosis of PC, which strongly regulated the progression and drug resistance of PC.